The cardiovascular and ventilatory responses to dynamic exercise are well known and include increases in sympathetic discharge to the vasculature, decreases in vagal discharge to the heart and airways as well as increases in tidal volume and breathing frequency. A reflex arising from the exercising muscles is believed to be mostly responsible for increases in sympathetic discharge to the vasculature, and probably contributes at least in part to the remaining effects. The overall aim of the proposed experiments is to determine the role played by mechanical and metabolic stimuli that arise in the dynamically exercising muscles in stimulating the thin fiber afferents (i.e., group III and IV) comprising the afferent arm of the reflex evoking these cardiovascular and ventilatory adjustments. Dynamic exercise will be induced in decerebrated unanesthetized cats by electrical and possibly chemical stimulation of the mesencephalic or subthalamic locomotor regions. [Three putative] metabolic stimuli will be investigated, namely lactic acid, ATP, a purine which stimulates P2 receptors, and bradykinin, a peptide that stimulates B2 receptors. The responses of group III and IV afferents to lactic acid will be blocked by both amiloride and A-317567, a compound reported to block acid sensing ion channels. Likewise, the responses of the afferents to ATP will be blocked by PPADS and suramin [and those to bradykinin will be blocked by HOE-140]. Each of the blocking agents will be injected into the popliteal artery perfusing the dynamically exercising triceps surae muscles. Afferent activity will be recorded from the L7-S1 dorsal roots both when the triceps surae muscles are freely perfused and when their circulation is occluded. Particular attention will be paid to a one minute period of post-exercise circulatory occlusion, which is a pure metabolic stimulus to group III and IV muscle afferents. The proposed studies should shed new light on the roles played by mechanical and metabolic stimuli in stimulating group III and IV muscle afferents during dynamic exercise. PUBLIC HEALTH RELEVANCE: We propose to determine the role played by mechanical and metabolic stimuli in evoking the cardiovascular and ventilatory responses to dynamic exercise (i.e., running). These responses are important because they support our ability to exercise in normal circumstances, but also can cause irregular heart rhythms, leading to death in patients with coronary artery disease. Increasing our understanding of the mechanisms causing these effects may lead to improved treatments for the cardiac problems occurring during exercise.